Abstract. To embellish diagnostic nuclear medicine imaging resources for detection of Alzheimer?s disease (AD), 18F- Florbetapir, 18F-Flutemetamol, and 18F-Florbetaben have gained FDA approval for A? imaging. However, among amyloid imaging agents, 11C-PIB continues to be the most thoroughly investigated PET tracer. Recent reports indicate that 11C-PIB and 18F-Florbetapir (MDC Study WUSTL) are not able to detect cerebral A? in patients confirmed via clinical, cognitive, and cerebrospinal fluid biomarkers of AD, thus raising concerns for sensitivity of PIB and other agents to detect AD variants characterized predominantly by diffuse A? plaques. Additionally, recent clinicopathological studies of a large cohort of PD patients also indicate limitations of PIB imaging to differentiate PD patients with or without dementia, despite the documented presence of abundant A? in brains of those patients post autopsy. Furthermore, a recent study from team of DIAN-TU and WUSTL investigators, wherein an extensive cross sectional and longtitudinal cross-over evaluation for 11C-PiB and 18F-Florbetapir was perfomed, it has been concluded that PiB PET imaging has a superior reliability for longtitudinal quantitative imaging (Please see letter from Dr. John Morris). This latter factor is enormously important for evaluating therapeutic efficacy and disease staging. Furthermore, anti-A? antibody based therapeutics have shown promising data in cognitive improvements of AD patients. While these disease modifying treatments act on different forms of A?, including diffuse A? plaques (a viable target at prodromal stages: please see letter from Dr. David Holtzman), current PET tracers lack capability to detect diffuse A? plaques in vivo, thus creating a gap in available PET imaging resources for quantitative detection of the disease at prodromal stages, and allow determination of therapeutic efficacy. To accomplish this objective, we have rationally designed a novel heterocyclic fluorescent molecule (18F-AI-187; named Fluselenamyl) belonging to an entirely new class of molecules that shows higher sensitivity (detects diffuse A? in PiB imaging negative but CSF biomarkers positive case; Figure 6, Research Strategy) and remarkable molecular specificity towards A? diffuse and fibrillar plaques, while also indicating far superior (5-fold) gray /white matter ratio of a PET signal than that of 11C-PIB in AD brain sections using autoradiography (Figure 9, Research Strategy). Finally, Fluselenamyl does not show any adverse effects either on blood chemistry or tissue sections of mice in 2 week single-injection toxicology studies thus desirable of translation from bench to the bedside. Armed with this provocative information, aims of this translational RO1 project focused on development of this novel PET tracer and its evaluation in humans are: 1) Perform three validation runs to ascertain chemistry manufacturing controls (CMCs) for producing the PET radiopharmaceutical, evaluation controls, and procedures for controls of the finished dosage forms for compiling information for eIND filing. 2) Perform radiation dosimetry studies in cognitively normal subjects (n=8; 4 Males, 4 Females) to calculate the effective safe dose (ED) for intravenous administration. 3) Perform proof of concept studies of 18F-Fluselenamyl to assess its sensitivity and molecular specificity for imaging A? pathophysiology in participants with mild cognitive impairment; MCI (n= 28, 14 Males, 14 Females), and conduct comparative analysis of PET imaging data, using 11C-PIB imaging in same participants. 4) Evaluate performance of 18F-Fluselenamyl for mapping plaque A? burden accurately with disease staging in participants (n= 36; 18 males and 18 females) via randomized test-retest (n = 12 to undergo repeat 18F-Fluselenamyl imaging with 2 weeks of baseline) and longitudinal imaging and clinical studies (n= 24, to undergo repeat 18F-Fluselenamyl, MRI, Cognitive testing approx. after 18 months of the baseline18F-Fluselenamyl imaging). Successful execution of outlined aims could provide an ultrasensitive, and a specific tool for quantitative A? imaging, while also providing noninvasive imaging tool for precise assessment of therapeutic efficacy for disease- modifying interventions. Although the potential applications of this versatile PET molecular signature could extend well-beyond AD, nevertheless it would enable sensitive and specific detection of AD at prodromal stages to better guide the management of this grave 21st century neurodegenerative disorder.